Intermediates and process for the preparation thereof

ABSTRACT

A process for the preparation of 2-[(2-thienyl)-ethylamino]-(2-halogenophenyl)-acetamides of general formula (VII) starting from the nitriles of general formula (I). Compounds of general formula (VII) are valuable intermediates.

This application is the national phase under 35 U.S.C. § 371 of PCTInternational Application No. PCT/HU98/00047 which has an Internationalfiling date of May 11, 1998, which designated the United States ofAmerica.

This invention relates to the new intermediates of general formula(VII), wherein X stands for halogen atom, and to the process of theirpreparation.

It is known that methyl(2-halogenophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetatesand their salts can favorably be used in the treatment, first of allowing to their platelet-aggregation-inhibitory and antithromboticeffect.

An especially favorable representative of these compounds, falling undergeneral formula (VI)—wherein X means chloro atom, is the dextrotatorymethyl(+)-[(S)-(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetatehdyrogen sulfate], with the international non-proprietary name (INN)clopidogrel (European patent application, Publication Nr. 099802).

Large-scale preparation of compounds of general formula (VI), wherein Xmeans halogen atom, was previously feasible only through the stronglylacrimatory and mucous membrane irritant α-halogenophenylacetic acidderivatives, which are difficult to handle and are unfavourable from ahealth and environmental perspective. (European patent applications,Publications Nos. 099802, 0420706, 0466569). Furthermore, yields of theknown methods are rather poor.

Our aim was to eliminate the use of the above unpleasant intermediates(such as for instance α-bromo-(2-chlorophenyl)acetic acid and its methylester) and to enhance substantially the yield of compounds of generalformula (VI) in the synthesis.

In the synthesis according to our present invention, each intermediateis chiral in the preparation of an optically active end-product, as forinstance clopidogrel, thus, the possibility is open to use, from thefirst step on, optically active compounds as intermediates. The economicbenefit of the method is, among others, the avoidance of preparation ofan unwanted isomer.

We have found that preparing the compounds of general formula (VI) bythe route shown on scheme 1, that the use of the unpleasantintermediates can be avoided, and in addition, the yield of thesynthesis is much higher. The subject of the present invention is thesecond section of reaction scheme 1.

The optically active compounds of general formula (VII) are preparedeither from the optically active compounds of general formula (I) by theprocess according to our invention, or by resolving the racemic compoundof general formula (VII) to its optical isomers.

According to our invention a racemic or optically active compound ofgeneral formula (I), wherein the meaning of X is as defined above, orits salts are transformed, and if desired, the resulting racemiccompound of general formula (VII) is resolved to its optically activeisomers, and if desired, the racemic compound or the optically activeisomers are transformed into their salts, or the racemic compound or theoptically active isomers are liberated from their salts.

The reaction of the compounds of general formula (I) with methanol andhydrochloric acid is performed in dry organic solvent. Alkyl acetatessuch as for instance methyl acetate or ethyl acetate may favorably beapplied as the organic solvent. The reaction is carried out at atemperature between 0° C. and +60° C., preferably between 10° C. and 50°C. The optically active compounds of general formula (VII) are preparedeither from the optically active compounds of general formula (I) by theroute according to our invention, or by resolution of the racemiccompound of general formula (VII). As for resolving agent numerouschiral acids may be applied, very advantageous is the application ofL-(+)-tartaric acid in the presence of formic acid and isopropanol.

Preparation of the compounds of general formula (I) is demonstrated inthe examples and in scheme 1. Starting materials (III), (IV) and (V) ofthe synthesis may be purchased, synthesis of the compound of formula(II) is described, e.g. in the French patent application publication No.2608607.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1A is a pictorial representation of general formula (VII);

FIG. 1B is a pictorial representation of general formula (VII); and

FIG. 2 is a pictorial representation of reaction scheme 1.

Further details of the invention are illustrated by the followingexamples, without limiting the scope of the invention to the examples.

EXAMPLE 1 [2-(2-thienyl)ethylamino](2-chlorophenyl)acetonitrile

104 g (1 mol) of sodium bisulfite is dissolved in the mixture of 900 mlof water and 250 mol of ethanol and to the solution 140.6 g (1 mol)o-chlorobenzaldehyde is added. After a few minutes the aldehydebisulfite adduct precipitates in the form of white crystals, while thetemperature increases to 40° C. After 1 hour of stirring 127.2 g (1 mol)of 2-(2-thienyl)ethylamine is added to the reaction mixture, then it wasstirred at 50° C. for 2 hours. During this time the crystalline aldehydebisulfite transforms into an oily material. The mixture is cooled toroom temperature and the solution of 49 g (1 mol) of sodium cyanide in100 ml of water is added to it. During the addition, the temperature ofthe reaction mixture increases to 40° C. The mixture is then stirred at60° C. Till the reaction is completed (1 hour). The oily organic phaseis then extracted with 400 ml of 1,2-dichloroethane, washed tocyanide-free with 2×200 ml of water. Traces of 2-(2-thienyl)ethylamineare removed by treatment with 100 ml of 3% hydrochloric acid solution.The dichloroethane phase was dried over anhydrous sodium sulfate andevaporated in vacuo. The residual fast crystallizing oil is the product.Weight: 260 g (94%) mp.: 40-41° C. The product was identified byelemental analysis, IR spectrum and ¹H-NMR investigation.

EXAMPLE 2 [2-(2-thienyl)ethylamino](2-chlorophenyl)acetonitrile

9.8 g (0.2 mol) of sodium cyanide is dissolved in 70 ml of water and tothe solution first 32.8 g (0.2 mol) of 2-(2-thienyl)ethylaminehydrochloride, then in a period of a few minutes, the solution of 28.2 g(0.2 mol) of o-chlorobenzaldehyde in 30 ml of ethanol are added. Duringthe addition the temperature of the mixture increases to 45° C. Thereaction mixture is then stirred at 60° C. for 2 hours, then cooled toroom temperature and diluted with 50 ml of water. The resulting oilyproduct is extracted with 100 ml of 1,2-dichloroethane. The organicphase is washed to cyanide-free with 2×50 ml of water. The traces of2-(2-thienyl)ethylamine are removed by treatment with 20 ml of 3%hydrochloric acid solution. The residual fast crystallizing oil is theproduct. Weight: 52 g (94%) mp.: 40-41° C. The product was identified aswritten in Example 1. Quality of the product is identical with that ofthe product prepared according to Example 1.

EXAMPLE 3 [2-(2-thienyl)ethylamino](2-chlorophenyl)acetonitrilehydrochloride

276.7 g (1 mol) of [2-(2-thienyl)ethylamino](2-chlorphenyl)acetonitrile,prepared according to example 1 or 2, is dissolved in 600 ml of ethanol,to the solution 600 ml of 10% aqueous hydrochloric acid solution isadded. Within a few minutes white crystals precipitate, then arecollected, washed with 60 ml of 1:1 mixture of 10% hydrochloric acid andethanol, then with acetone, and they are dried. Weight 305 g (97.4%),mp: 153-154° C. The product was identified by elemental analysis, IRspectrum and ¹H-NMR investigation.

EXAMPLE 4 [2-(2-thienyl)ethylamino](2-chlorophenyl)acetonitrilehydrobromide

13.8 g (0.05 mol) of[2-(2-thienyl)ethylamino](2-chlorophenyl)acetonitrile, preparedaccording to example 1 or 2, is dissolved in 30 ml of ethanol, to thesolution 40 ml of 20% aqueous hydrogen bromide solution is added. Theproduct which precipitates within a few minutes is collected, washedwith ethyl acetate and then they are dried. Weight: 14 g (78.2%), mp.:144-145° C. The product was identified by elemental analysis, IRspectrum and ¹H-NMR investigation.

EXAMPLE 5 [2-(2-thienyl)ethylamino](2-chlorophenyl)acetonitrilehydrochloride

Into 1200 ml of methyl acetate 204 g (5.6 mol) of hydrogen chloride gasis introduced at 15-25° C., and to the solution 221.4 g (0.8 mol) of the[2-(2-thienyl)ethylamino](2-chlorophenyl)acetonitrile of formula (I),prepared as described in Example 1, and 48 ml (1.2 mol) of methanol areadded and the mixture is stirred at 20-25° C. for 6 hours. In the courseof the reaction first the hydrochloride of the stating “nitrile”, thengradually the hydrochloride of the resulting “acid amide” precipitates,in the form of white crystals. The crystals are collected by filtration,washed with methyl acetate and dried. Weight: 249 g (94%) mp.: 231-232°C.

The product was identified by elemental analysis, IR spectrum and ¹H-NMRinvestigation.

EXAMPLE 6 [2-(2-Thienyl)ethylamino](2-chlorophenyl)acetonitrilehydrochloride

Into 700 ml ethyl acetate at 0-10° C. 109.8 g (3 mol) of hydrogenchloride gas was introduced and to the solution 83 g (0.3 mol) of the[2-(2-thienyl)ethylamino](2-chlorophenyl)acetonitrile of formula (I),prepared according to Example 1 or 2, and 15 ml (0.37 mol) of methanolare added and the mixture is slowly, in a period of 20 minutes, heatedto 45-50° C. the reaction mixture is then stirred at 45-50° C. for 4hours, the crystalline product is filtered off at room temperature,washed with ethyl acetate and dried. Weight: 90.4 g (91%) op.: 231-232°C. The quality of the product is identical with that of the product ofExample 5.

EXAMPLE 7 [2-(2-Thienyl)ethylamino](2-chlorophenyl)acetamide

24.8 g (0.075 mol) of [2-(2-thienyl)ethylamino](2-chlorophenyl)acetamidehydrochloride, prepared according to example 5 or 6, is mixed with 170ml of water, then under mild cooling 30 ml of 10% sodium hydroxidesolution and 170 ml of 1,2-dichloroethane are added. The phases areseparated, the aqueous phase is extracted with 2×20 ml of1,2-dichloroethane, the combined organic layer is evaporated in vacuo.Residue: 22 g, fast crystallizing oil. The raw product is recrystallizedfrom 80 ml of isopropyl acetate to give 19.5 g of the crystalline baseof formula (VII). Yield: 88.2%, mp.: 90-92° C.

The product was identified by elemental analysis, IR spectrum and ¹H-NMRinvestigation.

EXAMPLE 8 [2-(2-thienyl)ethylamino](2-chlorophenyl)acetamidehydrobromide

14.7 g (0.05 mol) of [2-(2-thienyl)ethylamino](2-chlorophenyl)acetamide,prepared as described in Example 7, is dissolve din 150 ml of acetone.To the solution 4 ml of 60% aqueous hydrogen bromide solution is addedand the precipitated white crystals are filtered off, washed withacetone and dried.

The product was identified by elemental analysis, IR spectrum and ¹H-NMRinvestigation.

EXAMPLE 9 Methyl [2-(2-thienyl)ethylamino](2-chlorophenyl)acetatehydrochloride

21.5 ml (0.4 mol) of 100% sulfuric acid is dissolved, under cooling in100 ml of methanol, the solution is heated under reflux for ½ hour, thencooled to room temperature and to it 33.1 g (0.1 mol) of[2-(2-thienyl)ethylamino](2-chlorophenyl)acetamide hydrochloride,prepared as described in Example 5, is added and the mixture is heatedunder reflux conditions for 10 hours. Methanol is then distilled off invacuo and to the residue 150 ml of 1,2-dichloroethane and 150 ml ofwater are added, shaken well, and the two phases are separated. Theaqueous layer is extracted with 2×30 ml of 1,2-dichloroethane, thecombined organic layers are washed with 80 ml of 5% sodium hydroxidesolution, then with 100 ml of water, dried over anhydrous sodium sulfateand evaporated in vacuo. Weight of the residue: 28.5 g. The oilyproduct, which is the base of formula (VIII), is dissolved in 50 ml ofisopropyl acetate, 7.3 ml (0.087 mol) of concentrated hydrochloric acidsolution is added to it, and the mixture is stirred at room temperaturefor 1 hour. The precipitating product is filtered off, washed with 2×10ml of isopropyl acetate and dried. Weight: 28.4 g (82%) mp.: 177-178° C.(lit. 175° C.).

The product was identified by elemental analysis, IR spectrum, ¹H-NMRand MS investigation and mp determination.

EXAMPLE 10 Methyl[2-(2-thienyl)ethylamino](2-chlorophenyl)acetatehydrochloride

In 150 ml of methanol 8.5 ml (0.15 mol) of 96% sulfuric acid isdissolved under cooling and the solution is then heated under refluxconditions for ½ hour. After cooling to room temperature 20 g (0.0678mol) of [2-(2-thienyl)ethylamino](2-chlorophenyl)acetamide, fallingunder general formula (VII) and prepared as described in Example 7, isadded to the solution, the mixture is placed into a closed apparatus(autoclave) and stirred at 130° C.—on for 5 hours, while the innerpressure elevates to 13 bar. The reaction mixture is then cooled to roomtemperature (remaining pressure 1-2 bar), the methanol is distilled offin vacuo and to the residue 100 ml of isopropyl acetate and 100 ml ofwater are added and the pH of the mixture is adjusted to 7.5 by dropwiseaddition of 60 ml of 10% sodium hydroxide solution, under cooling andstirring, while keeping the mixture at room temperature. The phases areseparated, the organic phase is stirred with 60 ml of 3% aqueous maleicacid solution at 40-50° C. for 10 minutes, the two phases are thenseparated. After re-extracting the aqueous maleic acid solution with 30ml so isopropyl acetate the organic layers are combined, dried overanhydrous sodium sulfate and concentrated to the half of its volume. Onaddition of 5 ml of conc. hydrochloric acid solution the productprecipitates as an oil which crystallizes within a few minutes. It iscooled to 0-(+5)° C. and after 2 hours the crystals are collected byfiltration, washed with a small amount of isopropyl acetate and dried.Weight: 19.4 g (82.5%) mp.: 177-178° C. The quality of the product issimilar to that of the material obtained in Example 9.

EXAMPLE 11 Methyl [2-(2-thienyl)ethylamino](2-chlorophenyl)acetatehydrobromide

The procedure as describe din Example 9 is followed, the resultingmethyl [2-(2-thienyl)ethylamino](2-chlorophenyl)acetate is dissolved in50 ml of isopropyl acetate, to the solution 8 ml of 62% aqueous hydrogenbromide solution is added and the mixture is stirred at room temperaturefor 1 hour. During this time the product crystallizes. The crystals arecollected, washed with 2×10 ml of isopropyl acetate and dried. Weight:32.5 g (83%) mp.: 164-165° C. The product was identified by elementalanalysis, IR spectrum and ¹H-NMR investigation.

EXAMPLE 12Methyl(2-chlorophenyl)(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetatehydrochloride hydrate

To 28.4 g (0.082 mol) of methyl[2-(2-thienyl)ethylamino](2-chlorophenyl)acetate hydrochloride, preparedaccording to example 9 or 10, are added 50 ml of 1,2-dichloroethane andthe solution of 7.5 g (0.09 mol) of sodium hydrogen carbonate in 100 mlof water. The mixture is stirred well, the phases are separated, theaqueous phase is washed with 2×30 ml of 1,2-dichloroethane, the combinedorganic layer is dried over anhydrous sodium sulfate and the solvent isremoved in vacuo. The residual 25 g material (acetate base) is dissolvedin 90 ml of formic acid, to the solution 4 g (0.13 mol) of paraformaldehyde is added and the mixture is stirred at 50° C. for 20minutes. The majority of the formic acid is then distilled off in vacuo,the residue is dissolved in the mixture of 100 ml of water and 100 ml of1,2-dichloroethane, the phases are separated, the aqueous phase isextracted again with 30 ml of 1,2-dichloroethane, the combined organicphase is shaken well with 100 ml of 5% sodium hdyrogen carbonatesolution, the phases are separated and the organic phase is dried overanhydrous sodium sulfate and evaporated in vacuo. The residue isdissolved in 45 ml of acetone and to the solution 6.5 ml (0.077 mol) ofconc. hydrochloric acid is added at 5-10° C., under cooling. The productslowly crystallizes. The mixture is stirred for 1 hour at 0-10° C., thenthe crystals are filtered off, washed with 2×10 ml of acetone and dried.Weight: 26.7 g (theoretical: 30.8 g ) Yield: 86.6%, mp.: 138-140° C.(literature mp: 130-140° C.). The product was identified by elementalanalysis, IR spectrum, ¹H-NMR investigation and melting pointdetermination.

EXAMPLE 13 Laevorotatory[2-(2-thienyl)ethylamino](2-chlorophenyl)acetonitrile hydrochloride

10 g (0.036 mol) of racemic[2-(2-thienyl)ethylamino](2-chlorophenyl)acetonitrile (I) is dissolvedin 15 ml of acetone, to the solution 10 g (0.043 mol) of(1R)-(−)-camphor-10-sulfonic acid and 0.5 ml (0.013 mol) of formic acidare added, the mixture is heated to 50-55° C., then after 1-2 minutes itis cooled to room temperature. Thus gradually precipitates the saltformed between the dextrorotatory enantiomer of the starting materialand (1R)-(−)-camphor-10-sulfonic acid, in an optically slightlycontaiminated form. The crystals are separated by filtration. To themother liquor 7 ml of methyl acetate containing 10% hydrogen chloride isadded, or calculated amount of dry hdyrogen chloride gas is introduced,the crystalline precipitate is filtered off, washed with acetone anddried. Weight: 2.5 g [α]²² _(D)=−43° (c=1, methanol). Yield: 43%,calculated on the laevarotatory enantiomer content of the startingmaterial.

After recrystallization from ethanol: [α]²² _(D)=−48° (c=1, methanol).Mp: 151-152° C. (decomposition). Optical purity<98% (determined by HPLCinvestigation).

The product was identified by elemental analysis, IR spectrum and ¹H-NMRinvestigation.

EXAMPLE 14 Dextrorotatory[2-(2-thienyl)ethylamino](2-chlorophenyl)acetonitrile hydrochloride

The procedure described in the previous example is followed, but asresolving acid (1S)-(+)-camphor-10-sulfonic acid is applied. Product:weight 2.5 g, [α]²² _(D)=+43° (c=1, methanol). Yield: 43%, calculated onthe dextrorotatory enantiomer content of the starting material. Afterrecrystallization from ethanol: [α]²² _(D)=+48° (c=1, methanol). Mp.:151-152° C. (decomposition). Optical purity>98% (determined by HPLCinvestigation).

The product was identified by elemental analysis, IR spectrum and ¹H-NMRinvestigation.

EXAMPLE 15 Dextrorotatory[2-(2-thienyl)ethylamino](2-chlorophenyl)acetamide

11.8 g (0.037 mol) of laevorotatory[2-(2-thienyl)ethylamino](2-chlorophenyl)acetonitrile hydrochloride issuspended in 100 ml of methyl acetate and 9.6 g of dry hydrogen chloridegas is introduced at room temperature. Following this 3.6 g (0.113 mol)of methanol is added and the mixture is stirred room temperature untilthe reaction is completed 6 hours. The precipitated crystallinematerial, the hydrochloride salt of the product, is then filtered off,suspended in water, neutralized with sodium hydrogen carbonate, understirring. The precipitated white crystalline raw product is filteredoff, dried and recrystallized from ethanol

Weight 5 g, [α]²² _(D)=+63° (c=1, methanol). Mp.: 122-124° C. yield:46%. Optical purity 97%.

The product was identified by elemental analysis, IR spectrum and ¹H-NMRinvestigation.

EXAMPLE 16 Dextrorotatory[2-(2-thienyl)ethylamino](2-chlorophenyl)acetamide

38 g (0.129 mol) of racemic[2-(2-thienyl)ethylamino](2-chlorophenyl)acetamide is dissolved at 50°C. in 380 ml of isopropanol containing 0-0.4% advantageously 0.2% ofwater and to this solution is added the 50° C. solution of 10.6 g (0.071mol) of L(+)-tartaric acid in 230 ml of isopropanol, containing 0-0.4%,advantageously 0.2% of water. The mixture is stirred at 50° C. for 30minutes. Thick, white precipitate is formed. To the mixture 3.4 ml (0.09mol) of formic acid is added and stirring is continued at 50° C. for 1hour. The reaction mixture is then cooled to room temperature, stirredfor another hour and the solid phase is filtered off. The precipitatedmaterial is the salt formed between the laevorotatory enantiomer of thestarting material and L(+)-tartaric acid, in an optically slightlycontaminated form. Weight: 30 g Mp.: 167-169° C., after crystallizationform ethanol. The mother liquor is evaporated in vacuo. The residue (29g) is taken up in 200 ml of water and 200 ml of 1,2-dichloroethane andneutralized under stirring with 16 g (0.19 mol) of sodium hydrogencarbonate. The phases are separated, the aqueous layer is washed with2×30 ml of 1,2-dichloroethane, the combined organic layer is extractedwith 50 ml of water, dried over anhydrous sodium sulfate and evaporatedin vacuo. Weight: 18 g. The raw product is recrystallized from 70 ml ofethanol, washed with a small amount of ethanol and dried. Weight: 12.6 gMp.: 122-124° C., [α]²² _(D)=+69° (c=1, methanol). Yield: 66.3%calculated on the dextrorotatory enantiomer content of the startingmaterial. Optical purity: 99-100%, usually higher than 98% (determinedby HPLCO).

The product was identified by elemental analysis, IR spectrum and ¹H-NMRinvestigation.

By concentration of the filtrate 4 g of racemic starting material can berecovered.

EXAMPLE 17 Dextrorotatory[2-(2-thienyl)ethylamino](2-chlorophenyl)acetamide

76 g (0.257 mol) of racemic[2-(2-thienyl)ethylamino](2-chlorophenyl)acetamide is dissolved at 50°C. in 1200 ml of isopropanol containing 0.2% of water and to thissolution 21.2 g (0.141 mol) of L(+)-tartaric acid and 8.3 g (0.18 mol)of formic acid are added. The mixture is stirred at 50° C. for 1 hourwhile thick white precipitate is formed. The reaction mixture is thencooled to room temperature during a period of 1 hour, stirred foranother 2 hours and the solid phase is filtered off.

The precipitated material is the salt formed between the laevorotatoryenantiomer of the starting material and L(+)-tartaric acid is anoptically slightly contaminated form. Weight: 57 g Mp.: 167-169° C.after crystallization from ethanol. After filtration of the former solidmaterial 5.2 g (0.141 mol) hydrochloric acid gas is introduced into thefiltrate to precipitate the hydrochloride of the product. The formedwhite crystallized material is filtered out and dried. Weight: 41.7 g.The obtained optically slightly contaminated salt is taken up in 100 mlof ethanol and 5.3 g (0.13 mol) of sodium hydroxide dissolved in 70 mlof ethanol is added into it gradually to release the free base. Theformed product containing some sodium chloride is filtered off andwashed with distilled water. After drying its weight is 27.7 g, 73% ofthe dextrorotatory enantiomer content of the starting material. Mp.:122-124° C., [α]²² _(D)=+69° (c=1, methanol).

If the ethanolic filtrate is evaporated in vacuo and the remains istaken up in water, 9 g of racemic starting material is recovered.

EXAMPLE 18 Dextrorotatorymethyl[2-(2-thienyl)ethylamino](2-chlorophenyl)acetate-hydrochloride

In 40 ml of methanol under cooling 11.5 ml (0.215 mol) of 100% sulfuricacid is dissolved, the solution is heated under reflux conditions for 30minutes, then after cooling to room temperature 12.4 g (0.042 mol) ofdextrorotatory [2-(2-thienyl)ethylamino](2-chlorophenyl)acetamide isadded and the mixture is heated under reflux for 6-7 hours, till the endof the reaction. Methanol is distilled off in vacuo, to the residue 75ml of 1,2-dichloroethane and 75 ml of water are added, the mixture isshaken well and the phases are separated. The aqueous phase is extractedwith 2×20 ml of 1,2-dichloroethane, the united organic phase isextracted with 50 ml of 5% sodium hydroxide solution then with 50 ml ofwater, dried over anhydrous sodium sulfate. The drying material isfiltered off and 1.5 g (0.041 mol of dry hydrogen chloride gas isintroduced under cooling into the solution. The precipitated crystallineproduct is filtered off, washed with 1,2-dichloroethane and dried.Weight: 12.1 g, mp.: 185-186° C. (decomposition), [α]²² _(D)=+107° .Yield: 83%. Optical purity: in general 99-100%.

The product was identified by elemental analysis, IR spectrum and ¹H-NMRinvestigation.

EXAMPLE 19 Dextrorotatory methyl α-(2-thienyl)ethylamino)(2-chlorophenyl)acetate through the resolution of the racemate

a) 175 g of the hydrochloride salt of compound of general formula(VIII)—wherein X means chloro atom—is dissolved in the mixture of 0.75liter of dichloroethane and 0.25 liter of water, and to the solution, 45g of sodium hydrogen carbonate is gradually added. After mixing, theorganic phase is separated by decantation. Following the usual work-upprocedure the amino-ester is obtained, which is then dissolved in 850 mlof acetone, and to the solution 87 g (+)-camphor-10-sulfonic acid isadded. The mixture is kept at room temperature for 12 hours and theresulting precipitate is separated. Thus 146.5 g of camphorsulfonate isobtained, [α]²² _(D)=+51.7° (c=1, methanol). The camphorsulfonate issuspended in 700 ml of acetone while heating under reflux conditions,and to achieve full dissolution 300 ml of methyl ethyl ketone is added.The mixture is allowed to cool down to room temperature. The resultingprecipitate is separated and treated at room temperature with 500 ml ofacetone and 300 ml of methyl ethyl ketone. Thus 95 g of the(+)-camphorsulfonate of the expected product is obtained, melting point:95° C., [α]²² _(D)=+82° (c=1, methanol).

b) 33.5 g of the hydrochloride salt of the compound of general formula(VIII)—wherein X means chloro atom—and 14,6 g (+)-tartaric acid aremixed in 500 ml of isopropanol, heated to 50° C., then allowed to stayat room temperature. The resulting precipitate is separated andcrystallized four times from isopropanol. Thus, the (+)-tartarate of thedesired dextrorotatory product is obtained, melting point: 105° C.Specific rotation of the amine [α]²⁰ _(D)=+99.76° (c=1, methanol).

EXAMPLE 20 Laevorotatory α-(2-thienyl)ethylamino) (2-chlorophenyl)aceticacid methyl ester through resolution of the racemate

100 g of the racemate hydrochloride of compound of general formula(VIII)—wherein X means chloro atom—and 30 g of sodium hdyrogen carbonateare mixed in 500 ml of dichloromethane and 200 ml of water. Afterstirring the organic phase is separated by decantation, and the solventis distilled off in vacuo. The residue is dissolved in 800 ml of acetoneand to this solution 53.3 g of (−)-camphor-10-sulfonic acid is added.The mixture is allowed to stay at room temperature of 12 hours. Theresulting precipitate is separated and suspended in 300 ml of acetone.The insoluble solid precipitate is crystallized from the mixture of 600ml of acetone and 160 ml of methyl ethyl ketone to obtained 52.5 of the(−)-camphorsulfonate of the desired product, melting point: 95° C.,[α]²² _(D)=−82° (c=1, methanol).

EXAMPLE 21(+)-(S)-(2-chlorophenyl(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)aceticacid methyl ester hdyrochloride salt

6 g (0.017 mol) of dextrorotatory methyl[2-(2-thienyl)ethylamino](2-chlorophenyl)acetate hydrochloride issuspended in 6.7 ml of 38% aqueous formaline solution and heated to 60°C. under stirring. The starting material dissolves at 60° C., theresulting solution is stirred at the temperature for 30 minutes, tillthe completion of the reaction. The reaction mixture is then dilutedwith 100 ml of 1.2 dichloroethane and 150 ml of water, and after shakingwell, the phases are separated. The aqueous phase is extracted with 2×30ml of 1,2-dichloroethane, the united organic phase is extracted with 100ml of water, dried over anhydrous sodium sulfate, filtered andevaporated in vacuo. The residual 6 g of material is dissolved in 30 mlof diethyl ether, and while cooling the reaction mixture, 0.6 g of dryhdyrogen chloride gas is introduced into the solution, at roomtemperature. The precipitated crystalline material is filtered off,washed with ether and dried. Weight: 5.5 g. Mp.: 130-132° C., [α]²²_(D)=+60°. Yield: 90.1%. Optical purity: 99% (by HPLC investigation).

EXAMPLE 22 a)(+)-(2-chlorophenyl(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetic acidmethyl ester (−)-camphorsulfonic acid salt

32 g (0.0994 mol ) of(2-chlorophenyl(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetic acidmethyl ester is dissolved in 150 ml of acetone and to the solution 9.95g (0.0397 mol ) of laevorotatory 10-camphorsulfonic acid monohydrate isadded. The homogenous reaction mixture is allowed to stay at roomtemperature. After 48 hours a few crystals appear. The mixture isconcentrated by evaporation to 50 ml and allowed to stay at roomtemperature for 24 hours. The resulting crystals are filtered off,washed with acetone and dried. The crystals thus obtained are dissolvedagain in a very small amount (50 ml) of hot acetone and after coolingthe crystals are filtered off, washed with acetone and dried. Thus thetitle compound is obtained. Yield: 88%. Mp.: 165° C. [α]²⁰ _(D)=+24°(c=1.68 g/100 ml: methanol).

b) (+)-(2-chlorophenyl(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)aceticacid methyl ester

To the suspension made of 200 g of(+)-(2-chlorophenyl(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetic acidmethyl ester (−)-camphorsulfonic acid salt and 800 ml of dichloromethaneis added 800 ml of sodium hydrogen carbonate solution. After stirringthe organic phase is separated by decantation, dried on sodium sulfateand the solvent is removed in vacuo. The(+)-(2-chlorophenyl(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetic acidmethyl ester is obtained as a solution in 800 ml of dichloromethane.After stirring, the organic phase is separated by decantation, driedover sodium sulfate and the solvent is removed in vacuo.

The (+)-(2-chlorophenyl)(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)aceticacid methyl ester is obtained in the form of colourless oil

c) (+)-(2-chlorophenyl)(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)aceticacid methyl ester hydrogen sulfate salt

The residue obtained in the previous example is dissolve din 500 ml ofice-cold acetone and to this solution 20.7 ml of concentrated sulfuricacid (93.64%; density 1.83) is added dropwise. The resulting precipitateis separated by filtration, washed with 1000 ml of acetone and dried ina vacuo oven at 50° C. Thus 139 g of the title salt is obtained in theform of white crystals. Mp.: 184° C., [α]²⁰ _(D)=+55.1° (c=1.891 g/100ml; methanol).

What is claimed is:
 1. Compounds of general formula (VII)

wherein the meaning of X is halogen atom—and their optical isomers andsalts.
 2. Laevorotatory optical isomers of compounds of general formula(VII)—wherein the meaning of X is halogen atom—and their salts. 3.Dextrorotatory optical isomers of compounds of general formula(VII)—wherein the meaning of X is halogen atom—and their salts. 4.(+)-[2-(2-thienyl)ethylamino]-(2-chlorophenyl)acetamide and its salts.5. (−)-[2-(2-thienyl)ethylamino]-(2-chlorophenyl)acetamide and itssalts.
 6. (+)-[2-(2-thienyl)ethylamino]-(2-chlorophenyl)acetamide andits salts.
 7. (+)-[2-(2-thienyl)ethylamino]-(2-chlorophenyl)acetamidehydrogen chloride. 8.(−)-[2-(2-thienyl)ethylamino]-(2-chlorophenyl)acetamide hydrogenchloride.
 9. Process for the preparation of compounds of general formula(VII),—wherein the meaning of X is halogen atom—characterized in that, aracemic or optically active compound of general formula (I)—wherein themeaning of X is as defined above—or their salts are transformed, and ifdesired, the resulting racemic compound of general formula (VII) isresolved to its optical isomers, and if desired, the racemic compound orits optical isomers are transformed into their salts, or the racemiccompound or its optical isomers are liberated from their salts.
 10. Theprocess defined in claim 9, characterized in that, the compounds ofgeneral formula (I) are reacted with methanol and hydrochloric acid. 11.The process defined in claim 9, characterized in that, the reaction iscarried out at a temperature between 0° C. and +60° C.
 12. The processdefined in claim 9, characterized in that, as organic solvent methylacetate or ethyl acetate is used.
 13. The process defined in claim 9,characterized in that, the compound of general formula (I) is applied inthe form of its slat.
 14. The process defined in claim 9, characterizedin that, a racemic compound of general formula (VII) is resolved withL-(+)-tartaric acid, in the presence of formic acid and isopropanol.